Nitric Oxide Amino Acid Esters for Improving Vascular Circulation, and Prophylaxis or Treatment of a Condition Associated with Impaired Blood Circulation

ABSTRACT

Use of nitric oxide amino acid esters for improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation, such as peripheral vascular disease. The nitric oxide amino acid esters may be co-administered with an antimicrobial in topical or transdermal compositions for improving vascular circulation, and prophylaxis or treatment of a condition associated with impaired blood circulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. provisional patent applications61/406,997, filed Oct. 26, 2010, and 61/406,998, filed Oct. 26, 2010,the specifications of which are hereby incorporated by reference.

BACKGROUND

(a) Field

The subject matter disclosed generally relates to compositions, and morespecifically to transdermal or topical compositions comprising nitricoxide amino acid ester compounds improving vascular circulation, andprophylaxis or treatment of a condition associated with impaired bloodcirculation.

(b) Related Prior Art

The decline in cardiovascular morbidity and mortality in the UnitedStates over the past three decades has been the result of significantadvances in research on cardiovascular disease mechanisms andtherapeutic strategies. However these advances have not been aspronounced in the treatment of peripheral vascular insufficiencies dueto the onset of various ailments such as diabetes, andarterioscleriosis. These peripheral insufficiencies result in variousdisease states and even amputation. The incidence of amputation relatedto peripheral vascular insufficiency and its related conditions isassociated with significant costs and significant impairment to theindividual. Worldwide prevalence estimates of amputation is difficult toobtain, mainly because amputation receives very little attention andresources in countries where survival is low (Aleccia 2010). The overallrates of amputation due to trauma or malignancy are decreasing while theincidence of dysvascular amputations is rising (Dillingham et al. 2002).Amputations due to dysvascular disease accounts from roughly 54% of limbloss cases in the United States, while traumatic amputations account for45% of loss (Aleccia 2010). The number of lower limb amputations isexpected to increase in the United States to 58,000 per year by 2030(Cutson and Bongiorni 1996; Fletcher et al., 2002), with nearly 75%occurring in those aged 65 and older (Clark et al. 1983).

The compounds administered for the treatment of diuresis, peripheralvascular disease (also known as peripheral arterial disease) anddiseases resulting from oxidative and/or endothelial dysfunctions oftenresult in toxic, chronic and/or debilitating side effects.Cardiovascular compounds such as ACE inhibitors, beta-adrenergicblockers, antithrombotic, thrombolytics, anticoagulants, antiplateletagents and vasodilator compounds or anti-hyperlipidemic compounds, show,for example, respiratory toxicity resulting in asthma and/or bronchitis,renal impairment, liver toxicity and other side effects. Hence there isa need in the art for compounds that have improved efficacy, lowertoxicity and that can be used at low dosages. The invention is directedto these, as well as other, important ends.

An ulcer is a sore on the skin or a mucous membrane, accompanied by thedisintegration of tissue. Ulcers can result in complete loss of theepidermis and often portions of the dermis and even subcutaneous fat. Anulcer that appears on the skin is often visible as an inflamed tissuewith an area of reddened skin. A skin ulcer is often visible in theevent of exposure to heat or cold, irritation, or a problem with bloodcirculation such as the cardiovascular diseases mentioned above. Forexample, due to lack of mobility, there is a prolonged pressure on thetissues, which causes a stress in the blood circulation which istransformed to a skin ulcer, commonly known as bedsores or decubitusulcers. Ulcers often become infected, and pus forms.

Nitric oxide (NO) donor molecules are well known vasodilators that cancontribute to improving blood circulation in an ulcerated area.Molecules such as nitroglycerin have been used to treat such conditions.However, in the case of nitroglycerin, there are several drawbacks tothe manufacture, storage and use of nitroglycerin. Nitroglycerin is anexplosive compound that is difficult to produce and stabilize. It isinherently unstable over the long term resulting in a maximum shelf lifeof a product containing of about six months.

A major drawback to the long term usage of nitroglycerin for thetreatment of diseases is that the metabolic pathway for the liberationof nitric oxide from nitroglycerin occurs in the mitochondria, utilizingthe aldehyde dehydrogenase 2 enzyme. The liberation of large amounts ofnitric oxide within the mitochondria from the use of nitroglycerinproves to be toxic to the mitochondria over time and eventually causesextensive metabolic disruption. Also, certain classes of patientsuffering from nitric oxide deficiencies, mainly of Asian descent, havebeen shown to carry a recessive allele of the gene producing aldehydedehydrogenase 2 which renders them non-responsive to the use ofnitroglycerin.

Therefore there still exists a need for an efficient replacementmolecules for nitroglycerin, but that would not possess the negativeaspects of nitroglycerin, such as poor stability, short half life andinherent toxicity. The use of such replacement molecules for thetreatment for dermatological ulcers, is highly desirable.

It is thus desirable to provide a composition and method for improvingvascular circulation, and prophylaxis or treatment of a conditionassociated with impaired blood circulation, which involves analternative compound to nitroglycerin, and does not require any specialoperational procedures other than the application of a composition.

It is thus desirable to provide a composition and method for improvingvascular circulation, and prophylaxis or treatment of a conditionassociated with impaired blood circulation which contains an alternativecompound to currently existing vasodilator compounds, and does notrequire any special operational procedures other than the application ofa composition.

SUMMARY

According to an embodiment, there is provided a method of a method ofimproving vascular circulation, and prophylaxis or treatment of acondition associated with impaired blood circulation in a patient whichcomprises:

(a) treating the patient with a therapeutically effective amount of acompound of formula (I)

wherein n may be 1 to 10;

wherein R₁ may be an amino acid side chain group (D or L configuration),

wherein R₂ may be a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond, or any pharmaceuticallyacceptable salts thereof.

The compound of formula (I) may be(2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 2′-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The method as claimed in claim 1, wherein said compound of formula (I)is 4′-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The R₂ may be a hydrogen atom.

The R₁ may be chosen from:

wherein when R₁ is

said R₁ may be also linked to an NH₂ of said Formula (I) to form aproline or hydroxyproline amino acid side chain.

The R₂ may be an amino acid of formula (II) (D or L configuration)forming a peptide bond:

wherein R_(x) may be chosen from

wherein when R₁ is

said R₁ may be also linked to an NH₂ of said Formula (I) to form aproline or hydroxyproline amino acid side chain.

The treating may be transdermally or topically.

The condition associated with impaired blood circulation may be chosenfrom a skin ulcer, a decubitus ulcer, a mouth ulcer, a diabetic footulcer, a venous insufficiency ulcer, a venous ulcer, an arterialinsufficiency ulcer, a neuropathic ulcer, a genital ulcer, a sore, awound, a peripheral vascular disease, an atherosclerosis, Raynaud'sphenomenon, an erythromelalgia and a gangrene.

The peripheral vascular disease may be associated with diabetes.

The patient may have a normotensive blood pressure, a hypertensive bloodpressure, or a hypotensive blood pressure.

The blood pressure may be a normotensive blood pressure or a hypotensiveblood pressure, and treating the patient results in a stable bloodpressure.

The blood pressure may be a hypertensive blood pressure, and treatingthe patient results in a decreased blood pressure.

The decreased blood pressure is a normotensive blood pressure.

According to another embodiment, there is provided a use of a compoundof formula (I) for the preparation of a medicament for the treatmentand/or alleviation of a peripheral vascular disease:

wherein n may be 1 to 10;

wherein R₁ may be an amino acid side chain group (D or L configuration),

wherein R₂ may be a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond,

or any pharmaceutically acceptable salts thereof.

According to another embodiment, there is provided a use of a compoundof formula (I) for the treatment and/or alleviation of a peripheralvascular disease:

wherein n may be 1 to 10;

wherein R₁ may be an amino acid side chain group (D or L configuration),

wherein R₂ may be a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond,

or any pharmaceutically acceptable salts thereof.

According to another embodiment, there is provided a use of a compoundof formula (I) for the preparation of a medicament for improvingvascular circulation, and prophylaxis or treatment of a conditionassociated with impaired blood circulation:

wherein n may be 1 to 10;

wherein R₁ may be an amino acid side chain group (D or L configuration),

wherein R₂ may be a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond,

or any pharmaceutically acceptable salts thereof.

According to another embodiment, there is provided a use of a compoundof formula (I) for improving vascular circulation, and prophylaxis ortreatment of a condition associated with impaired blood circulation:

wherein n may be 1 to 10;

wherein R₁ may be an amino acid side chain group (D or L configuration),

wherein R₂ may be a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond,

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be(2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 2′-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 4′-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) wherein R₂ may be a hydrogen atom.

The compound of formula (I), wherein R₁ is chosen from:

wherein when R₁ is

said R₁ may be linked to an NH₂ of said Formula (I) to form a proline orhydroxyproline amino acid side chain.

The R₂ may be an amino acid of formula (II) (D or L configuration)forming a peptide bond:

wherein R_(x) may be chosen from;

wherein when R₁ is

said R₁ may be also linked to an NH₂ of said Formula (I) to form aproline or hydroxyproline amino acid side chain.

The condition associated with impaired blood circulation may be chosenfrom a skin ulcer, a decubitus ulcer, a mouth ulcer, a diabetic footulcer, a venous insufficiency ulcer, a venous ulcer, an arterialinsufficiency ulcer, a neuropathic ulcer, a genital ulcer, a sore, awound, a peripheral vascular disease, an atherosclerosis, Raynaud'sphenomenon, erythromelalgia and a gangrene.

The peripheral vascular disease may be associated with diabetes.

According to another embodiment, there is provided a topical compositionfor improving vascular circulation and prophylaxis or treatment ofperipheral vascular disease and a condition associated with impairedblood circulation comprising:

(a) an effective amount of a compound of formula (I):

wherein n may be 1 to 10;

wherein R₁ may be an amino acid side chain group (D or L configuration),

wherein R₂ may be a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond, or any pharmaceuticallyacceptable salts thereof; and

(b) at least one topical antimicrobial,

in association with a pharmaceutically acceptable topical carrier.

The compound of formula (I) may be(2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 2′-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The compound of formula (I) may be 4′-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.

The R₂ may be a hydrogen atom.

The R₁ may be chosen from:

wherein when R₁ is

said R₁ may be also linked to an NH₂ of said Formula (I) to form aproline or hydroxyproline amino acid side chain.

The R₂ may be an amino acid of formula (II) (D or L configuration)forming a peptide bond:

wherein R_(x) may be chosen from;

wherein when R₁ is

said R₁ may be also linked to an NH₂ of said Formula (I) to form aproline or hydroxyproline amino acid side chain.

The topical antimicrobial may be at least one of a topical antibiotic, atopical antifungal, and combinations thereof.

The topical antibiotic may be chosen from Amikacin, Gentamicin,Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Geldanamycin,Herbimycin, Loracarbef, Ertapenem, Doripenem, Imipenem/Cilastatin,Meropenem, Cefadroxil, Cefazolin, Cefalotin, Cefalexin, Cefaclor,Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir,Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftobiprole,Teicoplanin, Vancomycin, Telavancin, Clindamycin, Lincomycin,Azithromycin, Clarithromycin, Dirithromycin, Erythromycin,Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Aztreonam,Furazolidone, Nitrofurantoin, Amoxicillin, Ampicillin, Azlocillin,Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin,Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V,Piperacillin, Temocillin, Ticarcillin, Amoxicillin and clavulanate,Ampicillin and sulbactam, Piperacillin and tazobactam, Ticarcillin andclavulanate, Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin,Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid,Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin,Temafloxacin, Mafenide, Sulfonamidochrysoidine, Sulfacetamide,Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole,Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim,Trimethoprim-Sulfamethoxazole, Demeclocycline, Doxycycline, Minocycline,Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin,Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide,Rifampicin, Rifabutin, Rifapentine, Streptomycin, Arsphenamine,Chloramphenicol, Fosfomycin, Fusidic acid, Linezolid, Metronidazole,Mupirocin, Platensimycin, Quinupristin/Dalfopristin, Rifaximin,Thiamphenicol, and Tinidazole.

The topical antifungal may be chosen from Natamycin, Rimocidin, Filipin,Nystatin, Amphotericin B, Candicin, Hamycin, Miconazole, Ketoconazole,Clotrimazole, Econazole, Bifonazole, Butoconazole, Fenticonazole,Isoconazole, Oxiconazole, Sertaconazole, Sulconazole, Tioconazole,Fluconazole, Itraconazole, Isavuconazole, Ravuconazole, Posaconazole,Voriconazole, Terconazole, Abafungin, Terbinafine, Amorolfine,Naftifine, Butenafine, Anidulafungin, Caspofungin, Micafungin, Benzoicacid, Ciclopirox, Tolnaftate, Undecylenic acid, 5-fluorocytosine,Griseofulvin, Haloprogin, and Sodium bicarbonate.

The skin penetration enhancer may be chosen from a C₈-C₂₂ fatty acid, aC₈-C₂₂ fatty alcohol, a lower alkyl ester of a C₈-C₂₂ fatty acid, adi(lower)alkyl ester of C₈-C₂₂ diacid, a monoglyceride of C₈-C₂₂ fattyacid, tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethyleneglycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol (transcutol),diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,an alkylaryl ether of polyethylene oxide, a polyethylene oxidemonomethyl ether, a polyethylene oxide dimethyl ether; dimethylsulfoxide (DMSO), glycerol, ethyl acetate, acetoacetic ester,N-alkylpyrrolidone, a terpenes, dimethyl formamide (DMF),N,N-dimethylacetamide (DMA), methyl laurate, glycerol monolaurate, afatty acid ester of a C₂ to C₄ alkanediol having a fatty acid portion ofsaid ester from about 8 to 22 carbon atoms, a fatty alcohol ether of aC₂ to C₄ alkanediols having a fatty acid portion of said ether fromabout 8 to 22 carbon atoms, triglycerides of coconut oil, isopropylpalmitate, isopropyl myristate, laurocapram, and combinations thereof.

The C₈-C₂₂ fatty acid may be chosen from isostearic acid, octanoic acid,and oleic acid.

The C₈-C₂₂ fatty alcohol may be chosen from oleyl alcohol and laurylalcohol.

The lower alkyl ester of a C₈-C₂₂ fatty acid may be chosen from ethyloleate, isopropyl myristate (IPM), butyl stearate, and methyl laurate.

The di(lower)alkyl esters of a C₈-C₂₂ diacid may be diisopropyl adipate.

The monoglyceride of a C₈-C₂₂ fatty acid may be glyceryl monolaurate.

The pharmaceutically acceptable carrier is chosen from a water base oran oil base carrier.

The composition may be further comprising a thickening agent.

The thickening agent may be chosen from CARBOPOL®, carboxypolymethylene,carboxymethylcellulose Carbopol® Ultrez 10, Carbopol® 940, Carbopol®941, Carbopol® 954, Carbopol® 980, Carbopol® 981, Carbopol® ETD 2001,Carbopol® EZ-2 and Carbopol® EZ-3.

The composition may be further comprising a wetting agent.

The wetting agent may be chosen from benzalkonium chloride, benzethoniumchloride, cetylpyridinium chloride; dioctyl sodium sulfosuccinate; apolyoxyethylene alkylphenyl ether, a poloxamers, a polyoxyethylene fattyacid glyceride, a polyoxyethylene alkyl ethers, a polyoxyethylene fattyacid ester, a polyoxyethylene sorbitan ester, a propylene glycol fattyacid ester, sodium lauryl sulfate, sodium laureth sulfate oleic acid,sodium oleate, triethanolamine oleate, a glyceryl fatty acid ester, asorbitan ester, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, tyloxapol and mixtures thereof.

The composition may be further comprising a lubricant.

The composition lubricant may be chosen from glyceryl behapate, stearicacid, magnesium stearate, calcium stearate, sodium stearate; ahydrogenated vegetable oil, colloidal silica, talc, a waxe, boric acid;sodium benzoate; sodium acetate; sodium fumarate; sodium chloride;DL-leucine; sodium oleate; sodium lauryl sulfate; magnesium laurylsulfate, glycerol, sorbitol, a water soluble cellulose, a polysorbate, acarbomer, a polyethylene glycol (PEG), a polyethylene, and a thickeningagent.

The water soluble cellulose may be chosen from modified starch,methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,Methocel® MC, carboxymethyl cellulose, ethyl cellulose, hydroxyl ethylcellulose, and any combination thereof.

The polysorbate may be chosen from polyoxyethylene (20) sorbitanmonolaurate (polysorbate 20), polyoxyethylene (20) sorbitanmonopalmitate (polysorbate 40), polyoxyethylene (20) sorbitanmonostearate (polysorban 60), polyoxyethylene (20) sorbitan tristrearate(polysorban 65), and polyoxyethylene (20) sorbitan monooleate(polysorban 80), and any combination thereof.

The carbomer may be a Carbopol® polymer chosen from Carbopol® polymer71G NF, Carbopol® polymer 971P NF, Carbopol® polymer 974P NF, Carbopol®polymer 980 NF, Carbopol® polymer 981 NF, Carbopol® polymer 5984 EP andCarbopol® polymer Ultrez 10 NF, and any combination thereof.

The polyethylene glycol (PEG) may be chosen from PEG 200, PEG 200E, PEG300, PEG 300E, PEG 400, PEG 400E, PEG 600 and PEG 600E, and anycombination thereof.

The thickening agent may be chosen from alginic acid, sodium alginate,potassium alginate, ammonium alginate, calcium alginate, agar,carrageenan, locust bean gum, xanthan gum, pectin, and gelatin, and anycombination thereof.

The composition may be further comprising at least one antiseptic agent.

The antiseptic agent may be selected from chlorhexidine gluconate,glucono delta-lactone, a paraben compound, benzoic acid, imidazolidinylurea, a quaternary ammonium compound, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride and Octenidinedihydrochloride.

The composition may be further comprising a preservative agent.

The preservative agent may be chosen from EDTA, EGTA, hydroxytoluenebutoxide, hydroxyanisol butoxide, sodium hydroxide, calcium propionate,sodium nitrate, sodium nitrite, sulfur dioxide, sodium bisulfite, andpotassium hydrogen sulfite.

The composition may be further comprising an emollient.

The emollient may be chosen from mineral oil, a mixture of a mineral oiland a lanolin alcohol, cetyl alcohol, cetostearyl alcohol, petrolatum,petrolatum and a lanolin alcohol, cetyl esters wax, cholesterol,glycerin, glyceryl monostearate, isopropyl myristate (IPM), isopropylpalmitate, lecithin, allyl caproate, althea officinalis extract,arachidyl alcohol, argobase EUC, butylene glycol, dicaprylate/dicaprate,acacia, allantoin, carrageenan, cetyl dimethicone, cyclomethicone,diethyl succinate, dihydroabietyl behenate, dioctyl adipate, ethyllaurate, ethyl palmitate, ethyl stearate, isoamyl laurate, octanoate,PEG-75, lanolin, sorbitan laurate, walnut oil, wheat germ oil, superrefined almond, super refined sesame, super refined soybean, octylpalmitate, caprylic/capric triglyceride, butyrospermum parkii oil, oliveoil, cetyl alcohol, behenyl alcohol, limnanthes alba seed oil, palmiticacid and glyceryl cocoate.

The composition may be further comprising a fragrance.

The composition may be one of a gel and a transdermal composition.

According to another embodiment, there is provided a method of treatingan ulcer in a patient which comprises:

-   -   (a) treating said patient with the composition according to the        present invention, to treat said ulcer.

The following terms are defined below.

The term “Amino acid ester compound” is intended to mean thecondensation product of an amino acid with mononitrated alkane ou alkenediol. As will be evident to those familiar to the art, the condensationreaction could also involve, but not limited to, dipeptides ortripeptides, nitrated alcohols containing aliphatic, alkyl or aromaticmoieties, as well as other nitric oxide groups attached to the alkane oralkene diols. Amino acid or dipeptide reactions are preferred as well asthe condensation reaction with short chain mononitrated alkane diolssuch as 1,3 propanediol or 1,4 butanediol.

The expression “Therapeutically effective amount” is intended to meanthe amount of the compound and/or composition that is effective toachieve its intended purpose.

The expression “Transdermally absorbed” is intended to mean the deliveryof a compound by passage through the skin and into the blood stream.

The terms “Carriers” or “vehicles” are intended to mean carriermaterials suitable for compound administration and include any suchmaterial known in the art such as, for example, any liquid, lotion, gel,solvent, liquid diluent, solubilizer, or the like.

The term “Nitric oxide adduct” or “NO adduct” is intended to meancompounds and functional groups which, under physiological conditions,can donate, release and/or directly or indirectly transfer any of thethree redox forms of nitrogen monoxide (NO⁺, NO⁻, NO*), such that thebiological activity of the nitrogen monoxide species is expressed at theintended site of action.

The term “Nitric oxide releasing” or “nitric oxide donating” is intendedto mean methods of donating, releasing and/or directly or indirectlytransferring any of the three redox forms of nitrogen monoxide (NO+,NO−, NO*), such that the biological activity of the nitrogen monoxidespecies is expressed at the intended site of action.

The term “Nitric oxide donor” or “NO donor” is intended to meancompounds that donate, release and/or directly or indirectly transfer anitrogen monoxide species, and/or stimulate the endogenous production ofnitric oxide or endothelium-derived relaxing factor (EDRF) in vivoand/or elevate endogenous levels of nitric oxide or EDRF in vivo and/orare oxidized to produce nitric oxide and/or are substrates for nitricoxide synthase and/or cytochrome P450. “NO donor” also includescompounds that are precursors of L-arginine, inhibitors of the enzymearginase and nitric oxide mediators.

The term “pharmaceutical acceptable carrier” is intended to mean apreservative solution, a saline solution, an isotonic (about 0.9%)saline solution, or about a 5% albumin solution, suspension, sterilewater, phosphate buffered saline, and the like. It is also intended tomean any aqueous or non-aqueous solvents that are suitable for deliveryof medicine to or into the target organ, as described herein. Otherbuffering agents, dispersing agents, and inert non-toxic substancessuitable for delivery to a patient may be included in the compositionsof the present invention. The compositions may be solutions, suspensionsor any appropriate formulation suitable for administration, and aretypically sterile and free of undesirable particulate matter. Thecompositions may be sterilized by conventional sterilization techniques.

The term “lubricant” is intended to mean a substance (often a liquid)introduced between two moving surfaces to reduce the friction betweenthem, hydrate the surface as well as reducing wear of the body parts.

The expression “improving vascular circulation” is intended to mean atherapeutic intervention that improves an impaired blood circulation inarteries, veins or both.

The expression “condition associated with impaired blood circulation” isany condition that may result from poor arterial and/or venous bloodflow, and may include for example ulcers caused by cold, heat,inflammation or irritation that may cause stress in the blood flow,wounds, sores, discoloration of the affected tissues, gangrene,necrosis, and the likes.

Features and advantages of the subject matter hereof will become moreapparent in light of the following detailed description of selectedembodiments, as illustrated in the accompanying figures. As will berealized, the subject matter disclosed and claimed is capable ofmodifications in various respects, all without departing from the scopeof the claims. Accordingly, the drawings and the description are to beregarded as illustrative in nature, and not as restrictive and the fullscope of the subject matter is set forth in the claims.

Further features and advantages of the present disclosure will becomeapparent from the following detailed description.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The composition of the present invention contains vasoactive amino acidester compounds. The nitric oxide amino acid ester compounds of thepresent invention possess many of the required characteristics necessaryto fulfill the role of a primary boosting of NO levels. The compoundseasily dissociate in water into the amino acid derivative and associatedion forming the pharmaceutical salt. The compounds of the presentinvention are extremely stable in the form of the salts, and thuspossess long shelf lives and stability.

The nitric oxide releasing groups of the compounds of the presentinvention are preferably nitro groups (i.e. NO₂), nitroso groups (i.e.NO) and/or heterocyclic nitric oxide donor groups that are linked to theamino acid ester compounds through one or more sites such as oxygen(hydroxyl condensation), sulfur (sulfhydryl condensation) and/ornitrogen. The heterocyclic nitric oxide donor groups are preferablyfuroxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.

The preferred compounds of the present invention are the valine ornorvaline derivatives of the nitric oxide amino acid ester of thepresent invention. The most preferred compounds are known as valinenitrooxy ethyl ester (or valine ethylene glycol nitrate), valinenitrooxy butyl ester (or valine butylene glycol nitrate), or anypharmaceutically acceptable salt thereof, which possess many of therequired characteristics necessary to fulfill the role of boosting NOlevels. The compound easily dissociates in water into the valinederivative valine ethylene or butylene glycol nitrate and the saltforming acid. The compounds are extremely stable in the form of the saltand thus possesses a long shelf life. It has been observed that thepreferred compounds of the present invention do not cause hypotension innormotensive or hypotensive individuals. Therefore, upon administrationof the preferred compounds of the present invention, an hypertensiveindividual will experience the vasodilatory effect caused by thepreferred compounds, which will result in a decrease in blood pressure.The decrease in blood pressure may be up to a normotensive bloodpressure. Individuals with normal blood pressure will not experience thevasodilatory effect caused by the preferred compounds, and their bloodpressure will remain stable (unchanged). Individuals with lower thannormal blood pressure (hypotensive) will not experience a further dropin blood pressure and their blood pressure will remain stable(unchanged). Furthermore, the preferred compounds of the presentinvention have half-life of approximately 5 hours. Preferably, atherapeutically effective amount of the compounds of the presentinvention are administered. Therapeutically effective amounts includebut are not limited to 0.5 to 30 mg of the compound of the presentinvention. Preferably, therapeutically effective amounts include 1 to 15mg, 0.5 to 5 mg, 1 to 5 mg, 5 to 10 mg, 10 to 15 mg, 1 to 15 mg, 1 to 30mg, 5 to 20 mg, 5 to 15 mg, 5 to 30 mg, 10 to 20 mg, 10 to 30 mg and 15to 30 mg. Other preferable therapeutically effective amounts alsoinclude from about 0.05 mg to about 200 mg, or from about 0.05 mg toabout 150 mg, or from about 0.05 mg to about 100 mg, or from about 0.05mg to about 50 mg, or from about 0.05 mg to about 40 mg, or from about0.05 to about 30 mg, or from about 0.05 mg to about 20 mg, or from about0.05 mg to about 15 mg, or from about 0.05 mg to about 10 mg, or fromabout 0.05 mg to about 5 mg, or from about 0.05 mg to about 1 mg, orfrom about 0.05 mg to about 0.5 mg, about 0.5 mg to about 200 mg, orfrom about 0.5 mg to about 150 mg, or from about 0.5 mg to about 100 mg,or from about 0.5 mg to about 50 mg, or from about 0.5 mg to about 40mg, or from about 0.5 to about 30 mg, or from about 0.5 mg to about 20mg, or from about 0.5 mg to about 15 mg, or from about 0.5 mg to about10 mg, or from about 0.5 mg to about 5 mg, or from about 0.5 mg to about1 mg, about 1 mg to about 200 mg, or from about 1 mg to about 150 mg, orfrom about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, orfrom about 1 mg to about 40 mg, or from about 1 to about 30 mg, or fromabout 1 mg to about 20 mg, or from about 1 mg to about 15 mg, or fromabout 1 mg to about 10 mg, or from about 1 mg to about 5 mg, about 5 mgto about 200 mg, or from about 5 mg to about 150 mg, or from about 5 mgto about 100 mg, or from about 5 mg to about 50 mg, or from about 5 mgto about 40 mg, or from about 5 to about 30 mg, or from about 5 mg toabout 20 mg, or from about 5 mg to about 15 mg, or from about 5 mg toabout 10 mg, about 10 mg to about 200 mg, or from about 10 mg to about150 mg, or from about 10 mg to about 100 mg, or from about 10 mg toabout 50 mg, or from about 10 mg to about 40 mg, or from about 10 toabout 30 mg, or from about 10 mg to about 20 mg, or from about 10 mg toabout 15 mg, about 15 mg to about 200 mg, or from about 15 mg to about150 mg, or from about 15 mg to about 100 mg, or from about 15 mg toabout 50 mg, or from about 15 mg to about 40 mg, or from about 15 toabout 30 mg, or from about 15 mg to about 20 mg, about 20 mg to about200 mg, or from about 20 mg to about 150 mg, or from about 20 mg toabout 100 mg, or from about 20 mg to about 50 mg, or from about 20 mg toabout 40 mg, or from about 20 to about 30 mg, about 30 mg to about 200mg, or from about 30 mg to about 150 mg, or from about 30 mg to about100 mg, or from about 30 mg to about 50 mg, or from about 30 mg to about40 mg, about 40 mg to about 200 mg, or from about 40 mg to about 150 mg,or from about 40 mg to about 100 mg, or from about 40 mg to about 50 mg,50 mg to about 200 mg, or from about 50 mg to about 150 mg, or fromabout 50 mg to about 100 mg, about 100 mg to about 200 mg, or from about100 mg to about 150 mg, or 150 mg to about 200 mg.

The compounds and compositions of the invention are described in moredetail herein.

The compounds and compositions of the invention can be formulated aspharmaceutically acceptable salt forms. Pharmaceutically acceptablesalts include, for example, alkali metal salts and addition salts offree acids or free bases. The nature of the salt is not critical,provided that it is pharmaceutically acceptable. Suitablepharmaceutically-acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of such inorganic acidsinclude, but are not limited to, hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriateorganic acids include, but are not limited to, aliphatic,cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classesof organic acids, such as, for example, formic, acetic, propionic,succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, mesylic, salicylic, p-hydroxybenzoic, phenylacetic,mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic,sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic,galactaric and galacturonic acid and the like. Suitable pharmaceuticallyacceptable base addition salts include, but are not limited to, metallicsalts made from aluminum, calcium, lithium, magnesium, potassium, sodiumand zinc or organic salts made from primary, secondary and tertiaryamines, cyclic amines, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine and the like. All of these salts may be prepared byconventional means from the corresponding compound by reacting, forexample, the appropriate acid or base with the compound. In oneembodiment, the pharmaceutically acceptable salts of the compounds ofthe invention include the nitrate salts. In another embodiment, thepharmaceutically acceptable salts of the compounds of the invention areheterocyclic compounds such as, furoxan, a sydnonimine, anoxatriazole-5-one and/or an oxatriazole-5-imine.

The compounds of the present invention, because of the small size of themolecule, can be other choices of linkages and/or amino acids or theirderivatives. For example, as alternatives to the above choices, propyl,butyl, or longer chains may be linked to any amino acid. Salts such aschloride or hydrochloride salts may be used. Other amino acidderivatives may also be chosen. Derivatives of the base amino acidswhether they are in the L or D configuration of these amino acids can bechosen. Non standard amino acids, or synthetic derivative of standardand non-standard amino acids may be elected, such as those containingacetyl groups attached to the amide of the molecule or nor derivativesof the amino acids, when such derivatives can be achieved.

The amino acid esters compounds may be based on natural, non-standard oreven modified amino acids, with the basic structure as depicted below,where the R_(x) represents the side chain of the amino acid (whereinR_(x) may be R₁, or R₂, as applicable to the specific molecule describedherein):

Basic Amino Acid Structure

Natural Amino Acids

Originating N° Amino acid Formula R_(x) = R₁ or R₂ 1 Glycine H —H 2Alanine CH₃

3 Valine* CH(CH₃)₂

4 Leucine* CH₂CH(CH₃)₂

5 Isoleucine* CH(CH₃)CH₂CH₃

6 Phenylalanine* CH₂C₆H₅

7 Tyrosine CH₂C₆H₄OH

8 Tryptophane* C₉H₈N

9 Serine CH₂OH

10 Threonine* CH(OH)CH₃

11 Cysteine CH₂SH

12 Methionine* CH₂CH₂SCH₃

13 Proline C₅H₉NO₂

14 Asparagine CH₂COCH₂

15 Glutamine CH₂CH₂CONH₂

16 Aspartic acid CH₂COOH

17 Glutamic acid CH₂CH₂COOH

18 Lysine* CH₂CH₂CH₂CH₂NH₂

19 Histidine* CH₃C₃N₂H₃

20 Arginine* (CH₂)₃CN₃H₄

*essential amino acids

Modified Amino Acids

Originating N° Amino acid Formula R_(x) = R₁ or R₂ A CystineCH₂S₂CH₂CHNH₂COOH

B Hydroxyproline C₅H₉NO₃

C ε-N-methyllysine CH₂CH₂CH₂CH₂NHCH₃

D diiodotyrosine CH₂C₆H₂I₂OH

E homocysteine CH₂CH₂SH

F ornithine CH₂CH₂CH₂NH₂

G Norvaline CH₂—CH₂—CH₃

H selenocysteine CH₂—SeH

I Hypusine CH₂CH₂CH₂CH₂NHCH₂CH(OH)CH₂CH₂NH₂

J Dehydroalanine CH₂

The nitric oxide amino acid ester compounds of the present invention arenot limited to a single amino acid molecule. The compounds of thepresent invention may be dipeptide or even tripeptide molecules, withthe general formula depicted below and where R_(x) and R_(y)independently are any of the amino acid side chains described herein.

The composition containing a compound as defined in the presentinvention may include a wide variety of additional components,including, for example, one or more of gases, gaseous precursors,liquids, oils, stabilizing materials, pharmaceutical acceptablecarriers, photoactive agents.

Compositions described herein also include those which are suitable fortransdermal administration of the compound as define in the presentinvention and optionally include a vehicle or carrier for thetransdermal administration of the compounds described herein as well asfurther comprising one or more of the following: pharmacologicallyactive agents, solvents, thickening agents, skin penetration enhancers,wetting agents, lubricants, emollients, substances added to mask orcounteract a disagreeable odor, fragrances, preservative agents andantiseptic agents.

According to another embodiment, the compositions described herein alsoinclude those which are suitable for topical administration, such as inthe form of gels and creams, for administration of the compound asdefined in the present invention and optionally include a vehicle orcarrier for the topical administration of the compounds described hereinas well as further comprising one or more of the following:pharmacologically active agents, solvents, thickening agents, skinpenetration enhancers, wetting agents, lubricants, emollients,substances added to mask or counteract a disagreeable odor, fragrances,preservative agents and antiseptic agents.

The compounds and compositions of the present invention can beadministered transdermally in dosage unit formulations containingconventional nontoxic pharmaceutically acceptable carriers, adjuvants,and vehicles, as desired. In one embodiment of the invention the aminoacid ester compound comprising at least one nitric oxide releasing groupis administered transdermally or topically.

Transdermal compound administration, which is known to one skilled inthe art, involves the delivery of pharmaceutical compounds viapercutaneous passage of the compound into the systemic circulation ofthe patient. Topical administration can also involve the use oftransdermal administration such as transdermal patches or iontophoresisdevices. Other components can be incorporated into the transdermalpatches as well. For example, compositions and/or transdermal patchescan be formulated with one or more preservatives or bacteriostaticagents including, but not limited to, methyl hydroxybenzoate, propylhydroxybenzoate, chlorocresol, benzalkonium chloride, and the like.Dosage forms for topical administration of the compounds andcompositions can include creams, sprays, lotions, gels, ointments, eyedrops, nose drops, ear drops, and the like. In such dosage forms, thecompositions of the invention can be mixed to form white, smooth,homogeneous, opaque cream or lotion with, for example, benzyl alcohol 1%or 2% (wt/wt) as a preservative, emulsifying wax, glycerin, isopropylpalmitat, lactic acid, purified water and sorbitol solution. Inaddition, the compositions can contain polyethylene glycol 400. They canbe mixed to form ointments with, for example, benzyl alcohol 2% (wt/wt)as preservative, white petrolatum, emulsifying wax, and tenox II(butylated hydroxyanisole, propyl gallate, citric acid, propyleneglycol). Woven pads or rolls of bandaging material, e.g., gauze, can beimpregnated with the compositions in solution, lotion, cream, ointmentor other such form can also be used for topical application.

The compositions can also be applied topically using a transdermalsystem, such as one of an acrylic-based polymer adhesive with a resinouscrosslinking agent impregnated with the composition and laminated to animpermeable backing. In a particular embodiment, the compositions of theinvention are administered as a transdermal patch, more particularly asa sustained-release transdermal patch. The transdermal patches of theinvention can include any conventional form such as, for example,adhesive matrix, polymeric matrix, reservoir patch, matrix ormonolithic-type laminated structure, and are generally comprised of oneor more backing layers, adhesives, skin penetration enhancers, anoptional rate controlling membrane and a release liner which is removedto expose the adhesives prior to application. Polymeric matrix patchesalso comprise a polymeric-matrix forming material. Suitable transdermalpatches are described in more detail in, for example, U.S. Pat. Nos.5,262,165; 5,948,433; 6,010,715 and 6,071,531.

Topical Antimicrobials

As used herein, “topical antimicrobials” refer to compounds that kill orinhibits the growth of microorganisms such as bacteria, fungi, orprotozoans. Antimicrobial drugs either kill microbes (microbicidal) orprevent the growth of microbes (microbistatic). Disinfectants areantimicrobial substances used on non-living objects. Antimicrobialsinclude compounds of diverse categories, such as antibiotics,antivirals, antifungals, antiparasitics. Preferably, the compositionaccording to the present invention will include at least one of anantibiotic and an antifungal.

Skin ulcers may take a very long time to heal and treatment typicallytries to avoid the ulcer getting infected. Topical antimicrobials,especially antibiotics, are normally used to prevent the ulcer gettinginfected and the wound or ulcer is usually kept clear of dead tissuethrough surgical debridement.

Antibiotics include in a non-limiting manner Amikacin, Gentamicin,Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Geldanamycin,Herbimycin, Loracarbef, Ertapenem, Doripenem, Imipenem/Cilastatin,Meropenem, Cefadroxil, Cefazolin, Cefalotin, Cefalexin, Cefaclor,Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir,Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime,Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftobiprole,Teicoplanin, Vancomycin, Telavancin, Clindamycin, Lincomycin,Azithromycin, Clarithromycin, Dirithromycin, Erythromycin,Roxithromycin, Troleandomycin, Telithromycin, Spectinomycin, Aztreonam,Furazolidone, Nitrofurantoin, Amoxicillin, Ampicillin, Azlocillin,Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin,Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V,Piperacillin, Temocillin, Ticarcillin, Amoxicillin and clavulanate,Ampicillin and sulbactam, Piperacillin and tazobactam, Ticarcillin andclavulanate, Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin,Gatifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid,Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin,Temafloxacin, Mafenide, Sulfonamidochrysoidine, Sulfacetamide,Sulfadiazine, Silver sulfadiazine, Sulfamethizole, Sulfamethoxazole,Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim,Trimethoprim-Sulfamethoxazole, Demeclocycline, Doxycycline, Minocycline,Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin,Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide,Rifampicin, Rifabutin, Rifapentine, Streptomycin, Arsphenamine,Chloramphenicol, Fosfomycin, Fusidic acid, Linezolid, Metronidazole,Mupirocin, Platensimycin, Quinupristin/Dalfopristin, Rifaximin,Thiamphenicol, and Tinidazole.

Antifungal include in a non-limiting manner Natamycin, Rimocidin,Filipin, Nystatin, Amphotericin B, Candicin, Hamycin, Miconazole,Ketoconazole, Clotrimazole, Econazole, Bifonazole, Butoconazole,Fenticonazole, Isoconazole, Oxiconazole, Sertaconazole, Sulconazole,Tioconazole, Fluconazole, Itraconazole, Isavuconazole, Ravuconazole,Posaconazole, Voriconazole, Terconazole, Abafungin, Terbinafine,Amorolfine, Naftifine, Butenafine, Anidulafungin, Caspofungin,Micafungin, Benzoic acid, Ciclopirox, Tolnaftate, Undecylenic acid,5-fluorocytosine, Griseofulvin, Haloprogin, and sodium bicarbonate.

Skin Penetration Enhancers

As used herein, “enhancement,” “skin penetration enhancement,” or “skinpermeation enhancement,” refer to an increase in the permeability of theskin to a drug, so as to increase the rate at which the drug permeatesthrough the skin. Thus, “skin permeation enhancer,” “skin penetrationenhancer,” or simply “enhancer” refers to an agent, or mixture of agentsthat achieves such permeation enhancement. Several compounds have beeninvestigated for use as skin penetration enhancers. See, for example,U.S. Pat. Nos. 5,601,839; 5,006,342; 4,973,468; 4,820,720; 4,006,218;3,551,154; and 3,472,931.

A skin penetration enhancer as used herein means any compound thataugments movement of active compound through the dermis, for instance,that allows a colloidal dispersion of lipid with a non-lipid so it canpenetrate body tissues which are composed of lipids and water along withother dermis components. In one embodiment, the skin penetrationenhancer is DMSO, however, any skin penetration enhancer suitable in andknown in the art for transdermal formulations may be used, such a thosethat allow a colloidal dispersion of a lipid with a non lipid so it canpenetrate body tissues which are composed of lipids and water along withother dermis components. In one embodiment, DMSO has been shown to be apreferred skin penetration enhancer and the invention provides atransdermal formulation or composition comprising a therapeuticcompound, or pharmaceutically acceptable salts thereof and DMSO with orwithout nano colloidal silica.

In one embodiment, the composition may comprise one or more skinpenetration enhancing agents for transdermal drug delivery. Non-limitingexamples of skin penetration enhancing agents include C₈-C₂₂ fatty acidssuch as isostearic acid, octanoic acid, and oleic acid; C₈-C₂₂ fattyalcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters ofC₈-C₂₂ fatty acids such as ethyl oleate, isopropyl myristate (IPM),butyl stearate, and methyl laurate; di(lower)alkyl esters of C₆-C₂₂diacids such as diisopropyl adipate; monoglycerides of C₈-C₂₂ fattyacids such as glyceryl monolaurate; tetrahydrofurfuryl alcoholpolyethylene glycol ether; polyethylene glycol, propylene glycol;2-(2-ethoxyethoxy)ethanol (transcutol); diethylene glycol monomethylether; alkylaryl ethers of polyethylene oxide; polyethylene oxidemonomethyl ethers; polyethylene oxide dimethyl ethers; dimethylsulfoxide; glycerol; ethyl acetate; acetoacetic ester;N-alkylpyrrolidone; terpenes, dimethyl formamide (DMF),N,N-dimethylacetamide (DMA), diethylene glycol monoethyl or monomethylether with propylene glycol monolaurate and methyl laurate; glycerolmonolaurate and ethanol, fatty acid esters or fatty alcohol ethers of C₂to C₄ alkanediols, where each fatty acid/alcohol portion of theester/ether is of about 8 to 22 carbon atoms.

The skin penetration enhancing agent is present in an amount sufficientto provide the desired physical properties and skin penetration profilefor the composition. Illustratively, one or more pharmaceuticallyacceptable skin penetration enhancer can be present in a total amount byweight of the composition of about 0.1%, about 0.2%, about 0.3%, about0.4%, about 0.5%, about 1.0%, about 1.5%, about 2.0%, about 2.5%, about3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%, about 5.5%, about6.0%, about 6.5%, about 7.0%, about 7.5%, about 8.0%, about 8.5%, about9.0%, about 9.5%, about 10.0%, about 10.5%, about 11.0%, about 11.5%,about 12.0%, about 12.5%, about 13.0%, about 13.5%, about 14.0%, about14.5%, and or 15.0%. As a further illustration, one or morepharmaceutically acceptable skin penetration enhancer is present in atotal amount by weight between about 0.1% and about 15%; between about0.1% and about 10%; between about 0.5% and about 10%; or between about3% and about 8%.

As a further illustration, one or more pharmaceutically acceptable skinpenetration enhancer is present in a total amount by weight betweenabout 1% and about 10%, between about 2% and about 10%, between about 3%and about 10%, between about 4% and about 10%, between about 5% andabout 10%, between about 6% and about 10%, between about 7% and about10%, between about 8% and about 10%, between about 9% and about 10%,between about 1% and about 9%, between about 2% and about 9%, betweenabout 3% and about 9%, between about 4% and about 9%, between about 5%and about 9%, between about 6% and about 9%, between about 7% and about9%, between about 8% and about 9%, between about 1% and about 8%,between about 2% and about 8%, between about 3% and about 8%, betweenabout 4% and about 8%, between about 5% and about 8%, between about 6%and about 8%, between about 7% and about 8%, between about 1% and about7%, between about 2% and about 7%, between about 3% and about 7%,between about 4% and about 7%, between about 5% and about 7%, betweenabout 6% and about 7%, between about 1% and about 6%, between about 2%and about 6%, between about 3% and about 6%, between about 4% and about6%, between about 5% and about 6%, between about 1% and about 5%,between about 2% and about 5%, between about 3% and about 5%, betweenabout 4% and about 5%, between about 1% and about 4%, between about 2%and about 4%, between about 3% and about 4%, between about 1% and about3%, between about 2% and about 3% and between about 1% and about 2%.

Thickening Agents

In one embodiment, the composition may comprise a thickening or gellingagent to increase the viscosity of the composition. None-limitingexamples of thickening agents (aka gelling agents) which may be usedherein include neutralized anionic polymers such as polyacrylic acid(CARBOPOL® by Noveon, Inc., Cleveland, Ohio), carboxypolymethylene,carboxymethylcellulose and the like, including derivatives of Carbopol®polymers, such as Carbopol® Ultrez 10, Carbopol® 940, Carbopol® 941,Carbopol® 954, Carbopol® 980, Carbopol® 981, Carbopol® ETD 2001,Carbopol® EZ-2 and Carbopol® EZ-3. Also suitable are other knownpolymeric thinking agents, such as Pemulen® polymeric emulsifiers, andNoveon® polycarbophils and Klucel®. Additional thickening agents,enhancers and adjuvants may generally be found in Remington's TheScience and Practice of Pharmacy as well as the Handbook ofPharmaceutical Excipients, Arthur H. Kibbe ed. 2000. Thickening agentsor gelling agents are present in an amount sufficient to provide thedesired rheological properties of the composition. Illustratively, oneor more pharmaceutically acceptable thickening agent or gelling agentare present in a total amount by weight of about 0.1%, about 0.25%,about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%,about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%,about 4.75%, about 5.0%, about 5.25%, about 5.5%, about 5.75%, about6.0%, about 6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%,about 7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75%, about 10%,about 11%, about 11.5%, about 12%, about 12.5%, about 13%, about 13.5%,about 14%, about 14.5% or about 15%. As a further illustration, one ormore pharmaceutically acceptable thickening or gelling agent are presentin a total amount by weight between about 0.1% and about 15%; about 0.5%and about 5%; or about 1% and about 3%.

Wetting Agents

Compositions described herein optionally comprise one or morepharmaceutically acceptable wetting agents as excipients. Non-limitingexamples of surfactants that can be used as wetting agents incompositions of the disclosure include quaternary ammonium compounds,for example benzalkonium chloride, benzethonium chloride andcetylpyridinium chloride; dioctyl sodium sulfosuccinate; polyoxyethylenealkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol9; poloxamers (polyoxyethylene and polyoxypropylene block copolymers);polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefossé), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether;polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate; polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI); propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefossé); sodium lauryl sulfate, sodium laureth sulfate, fatty acidsand salts thereof, for example oleic acid, sodium oleate andtriethanolamine oleate; glyceryl fatty acid esters, for example glycerylmonostearate; sorbitan esters, for example sorbitan monolaurate,sorbitan monooleate, sorbitan monopalmitate and sorbitan monostearate;tyloxapol; and mixtures thereof. Such wetting agents, if present,constitute in total about 0.25% to about 15%, about 0.4% to about 10%,or about 0.5% to about 5%, of the total weight of the composition.Illustratively, one or more pharmaceutically acceptable wetting agentsare present in a total amount by weight of about 0.25%, about 0.5%,about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%, about 2.0%,about 2.25%, about 2.5%, about 2.75%, about 3.0%, about 3.25%, about3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%, about 4.75%,about 5.0%, about 5.25%, about 5.5%, about 5.75%, about 6.0%, about6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%, about 7.5%,about 7.75%, about 8.0%, about 8.25%, about 8.5%, about 8.75%, about9.0%, about 9.25%, about 9.5%, about 9.75% or about 10%.

Lubricants

Compositions described herein optionally comprise one or morepharmaceutically acceptable lubricants (including anti-adherents and/orglidants) as excipients. Suitable lubricants include, eitherindividually or in combination, glyceryl behapate (e.g., Compritol™888); stearic acid and salts thereof, including magnesium (magnesiumstearate), calcium and sodium stearates; hydrogenated vegetable oils(e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodiumbenzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine;PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodiumlauryl sulfate; sodium laureth sulfate and magnesium lauryl sulfate.Such lubricants, if present, constitute in total about 0.1% to about10%, about 0.2% to about 8%, or about 0.25% to about 5%, of the totalweight of the composition. Illustratively, one or more pharmaceuticallyacceptable lubricants are present in a total amount by weight of about0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about4.9%, about 5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about5.5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6.0%, about6.1%, about 6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about6.7%, about 6.8%, about 6.9%, about 7.0%, about 7.1%, about 7.2%, about7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about7.9%, about 8.0%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9%, about 9.0%, about9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about9.7%, about 9.8%, about 9.9% or about 10.0%.

Emollients

In another embodiment, the compositions described herein optionallycomprise an emollient. Illustrative emollients include mineral oil,mixtures of mineral oil and lanolin alcohols, cetyl alcohol, cetostearylalcohol, petrolatum, petrolatum and lanolin alcohols, cetyl esters wax,cholesterol, glycerin, glyceryl monostearate, isopropyl myristate (IPM),isopropyl palmitate, lecithin, allyl caproate, althea officinalisextract, arachidyl alcohol, argobase EUC, butylene glycol,dicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyldimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate,dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, isoamyllaurate, octanoate, PEG-75, lanolin, sorbitan laurate, walnut oil, wheatgerm oil, super refined almond, super refined sesame, super refinedsoybean, octyl palmitate, caprylic/capric triglyceride and glycerylcocoate.

An emollient, if present, is present in the compositions describedherein in an amount of about 1% to about 30%, about 3% to about 25%, orabout 5% to about 15%, by weight. Illustratively, one or more emollientsare present in a total amount by weight of about 1%, about 2%, about 3%,about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, orabout 30%.

Water Soluble Celluloses

Celluloses are organic compounds with the general formula (C₆H₁₀O₅)_(n),a polysaccharide consisting of a linear chain of several hundred to overten thousands β(1→4) linked D-glucose units. Preferred cellulosesinclude water-soluble celluloses, and modified water-soluble cellulosessuch as those known in the art and have properties similar to cellulose.Examples are methylcellulose of different viscosity, ethylcellulose,hydroxypropyl cellulose, hydroxymethylcellulose, andhydroxyethylcellulose, hydroxypropyl methylcellulose, Methocel® MC, andcarboxymethylcellulose. These cellulose compounds, like celluloseitself, are not digestible by humans, and they are not toxic, and notallergenic.

Polysorbates

Polysorbates are a class of emulsifiers used in some pharmaceuticals andfood preparation. Polysorbates are oily liquids derived from PEG-ylatedsorbitan (a derivative of sorbitol) esterified with fatty acids.Polysorbates include but are not limited to polyoxyethylene (20)sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitanmonopalmitate (polysorbate 40), polyoxyethylene (20) sorbitanmonostearate (polysorban 60), polyoxyethylene (20) sorbitan tristrearate(polysorban 65), and polyoxyethylene (20) sorbitan monooleate(polysorban 80).

Carbomers

Carbomer is a generic name for synthetic polymers of acrylic acid usedas emulsion stabilizers or thickening agents in pharmaceuticals andcosmetic products. They may be homopolymers of acrylic acid, crosslinkedwith an allyl ether pentaerythritol, allyl ether of sucrose, or allylether of propylene. Carbomers include but are not limited to Carbopol®polymer 71G NF, Carbopol® polymer 971P NF, Carbopol® polymer 974P NF,carbopole polymer 980 NF, Carbopol® polymer 981 NF, Carbopol® polymer5984 EP and Carbopol® polymer Ultrez 10 NF.

Polyethylene Glycol (PEG)

PEG refers to an oligomer or polymer of ethylene oxide and are preparedby polymerization of ethylene oxide and are commercially available overa wide range of molecular weights from 300 g/mol to 10,000,000 g/mol.The preferred PEG to be used in the present invention are liquid PEGsincluding but not limited to PEG 200, PEG 200E, PEG 300, PEG 300E, PEG400, PEG 400E, PEG 600 and PEG 600E. The present invention will be morereadily understood by referring to the following examples which aregiven to illustrate the invention rather than to limit its scope.

Antiseptic Agents

The composition of the present invention may also be prepared by theaddition of an antiseptic agent in order to keep the composition sterileand disinfect the surfaces onto which it is applied during use. Thepreferred antiseptic agents include but are not limited to chlorhexidinegluconate, glucono delta-lactone, a paraben compound, benzoic acid,imidazolidinyl urea, a quaternary ammonium compound, methylhydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkoniumchloride and Octenidine dihydrochloride.

Preservative Agent

Furthermore, in order to stabilize and keep the composition for extendedperiods of time, preservative agents may be added to the composition.The preferred preservative agents include but are not limited to EDTA,EGTA, hydroxytoluene butoxide, hydroxyanisol butoxide, sodium hydroxide,calcium propionate, sodium nitrate, sodium nitrite, sulfur dioxide,sodium bisulfite, benzoic acid, caprylyl glycol, Diazolidinyl urea,Phenoxyethanol, Dehydroacetic acid, Iodopropynylbutylcarbamate, Sorbicacid, Isopropyl-paraben, Isobutyl-paraben, Butyl-paraben, and potassiumhydrogen sulfite.

Use of the Composition

According to one embodiment, the method and the compositions of thepresent invention are used for improving vascular circulation, andprophylaxis or treatment of a condition associated with impaired bloodcirculation in a patient by treating transdermally the patient with acomposition according to an embodiment of the present invention to treatand/or alleviate the symptoms of peripheral vascular disease.

Preferably, the method and the compositions are for prophylaxis ortreatment of Peripheral vascular disease (PVD), commonly referred to asperipheral arterial disease (PAD) and rarely referred to as peripheralartery occlusive disease (PAOD), refers to the obstruction of largearteries not within the coronary or aortic arch vasculature. PVD canresult from atherosclerosis, inflammatory processes leading to stenosis,an embolism, or thrombus formation. It causes either acute or chronicischemia (lack of blood supply). Often PAD is a term used to refer toatheresclortic blockages found in the lower extremity. PVD also includesa subset of diseases classified as microvascular diseases resulting fromepisodal narrowing of the arteries (Raynaud's phenomenon), or wideningthereof (erythromelalgia), i.e. vascular spasms.

Typical symptoms of PVD include claudication, characterized by pain,weakness, numbness, or cramping in muscles of the limbs due to decreasedblood flow. The affected limb(s) display sores, wounds, or ulcers thatheal slowly or not at all, and they also have a noticeable change incolor (blueness or paleness) or temperature (coolness) when compared tothe other limbs. Furthermore, there is diminished hair and nail growthon affected limb and digits.

PVD has a number of causations, which include tobacco use, which in anyform is the single most important modifiable cause of PVDinternationally. Smokers have up to a tenfold increase in relative riskfor PVD in a dose-related effect. Exposure to second-hand smoke fromenvironmental exposure has also been shown to promote changes in bloodvessel lining (endothelium) which is a precursor to atherosclerosis.

Diabetes mellitus is also associated with PVD as individuals withdiabetes mellitus have between two and four times increased risk of PVDby causing endothelial and smooth muscle cell dysfunction in peripheralarteries. Diabetics account for up to 70% of nontraumatic amputationsperformed, and a known diabetic who smokes runs an approximately 30%risk of amputation within 5 years.

The elevation of total cholesterol, LDL cholesterol, and triglyceridelevels (collectively referred to as dyslipidemia) each have beencorrelated with accelerated PVD. Correction of dyslipidemia by dietand/or medication is associated with a major improvement in short-termrates of heart attack and stroke.

Elevated blood pressure (hypertension) is correlated with an increase inthe risk of developing PVD, as well as in associated coronary andcerebrovascular events (heart attack and stroke). Other risk factorswhich are being studied include levels of various inflammatory mediatorssuch as C-reactive protein, homocysteine, and an over active sex lifemay increase risk of contracting PVD. Risk of PVD also increases if thepatient is: over the age of 50, African American, male, obese, or has apersonal history of vascular disease, heart attack, or stroke.

In embodiments, the composition of the present invention is used totopically treat the affected limb or area in order to increasevasodilatation of the blood vessels and improve blood flow therein.

According to another embodiment, the compositions of the presentinvention are also used for treating ulcers in a patient. The patientmay be treated topically with a gel or a cream according to the presentinvention, and/or treating the patient transdermally with thecomposition according to an embodiment of the present invention to treatthe ulcer.

Skin ulcers appear as open craters, often round, with layers of skinthat have eroded. The skin around the ulcer may be red, swollen andtender. Patients may feel pain on the skin around the ulcer, and fluidmay ooze from the ulcer. In some cases, ulcers can bleed and, rarely,patients experience fever. Ulcers sometimes seem not to heal; healing,if it does occur, tends to be slow. Ulcers that heal within 12 weeks areusually classified as acute, and longer-lasting ones as chronic.

Chronic ulcers may be painful. Most patients complain of constant painat night and during the day. Chronic ulcers symptoms usually includeincreasing pain, friable granulation tissue, and foul odour and woundbreakdown instead of healing. Symptoms tend to worsen once the wound hasbecome infected. Venous skin ulcers that may appear on the lower leg,above the calf or on the lower ankle usually cause achy and swollenlegs. If these ulcers become infected they may develop an unpleasantodour, increased tenderness and redness. Before the ulcer establishesdefinitively, there may be a dark red or purple skin over the affectedarea as well as a thickening, drying and itchy skin.

Although skin ulcers do not seem of great concern at a first glance,they are worrying conditions especially in people suffering fromdiabetes, as they are at risk of developing diabetic neuropathy.Diabetic foot ulcer is one of the major complications of Diabetesmellitus. It occurs in 15% of all patients with diabetes and precedes84% of all lower leg amputations. Diabetic foot ulcers, occur as aresult of various factors. Such factors include mechanical changes inconformation of the bony architecture of the foot, peripheralneuropathy, and atherosclerotic peripheral arterial disease, all ofwhich occur with higher frequency and intensity in the diabeticpopulation.

Ulcers may also appear on the cheeks, soft palate, the tongue, on theinside of the lower lip, and sometimes on other mucous membranes. Theseulcers usually last from 7 to 14 days and can be painful.

The wounds from which ulcers arise can be caused by a wide variety offactors, such as heat, cold, inflammation and prolonged pressure on thetissue, but the main cause is impaired blood circulation.

Ulcer include a skin ulcer, a decubitus ulcer, a mouth ulcer, a diabeticfoot ulcer, a venous insufficiency ulcer, a venous ulcer, an arterialinsufficiency ulcer, a neuropathic ulcer, a genital ulcer.

Other condition associated with impaired blood circulation includesores, and wounds, peripheral vascular disease, atherosclerosis,Raynaud's phenomenon, and gangrene.

While preferred embodiments have been described above and illustrated inthe accompanying drawings, it will be evident to those skilled in theart that modifications may be made without departing from thisdisclosure. Such modifications are considered as possible variantscomprised in the scope of the disclosure.

1. A method of improving vascular circulation, and prophylaxis ortreatment of a condition associated with impaired blood circulation in apatient which comprises: (a) treating said patient with atherapeutically effective amount of a compound of formula (I)

wherein n=1 to 10; wherein R₁ is an amino acid side chain group (D or Lconfiguration), wherein R₂ is a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond, or any pharmaceuticallyacceptable salts thereof.
 2. The method as claimed in claim 1, whereinsaid compound of formula (I) is(2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.
 3. The method asclaimed in claim 1 wherein said compound of formula (I) is valinebutylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.
 4. The method asclaimed in claim 1, wherein said compound of formula (I) is:

or any pharmaceutically acceptable salts thereof.
 5. The method asclaimed in claim 1, wherein said compound of formula (I) is2′-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.
 6. The method asclaimed in claim 1, wherein said compound of formula (I) is4′-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.
 7. (canceled)
 8. Themethod as claimed in claim 1, wherein R₁ is chosen from:

wherein when R₁ is

said R₁ is also linked to an NH₂ of said Formula (I) to form a prolineor hydroxyproline amino acid side chain.
 9. (canceled)
 10. The methodaccording to claim 1, wherein said treating is transdermally ortopically.
 11. The method as claimed in claim 1, wherein said conditionassociated with impaired blood circulation is chosen from a skin ulcer,a decubitus ulcer, a mouth ulcer, a diabetic foot ulcer, a venousinsufficiency ulcer, a venous ulcer, an arterial insufficiency ulcer, aneuropathic ulcer, a genital ulcer, a sore, a wound, a peripheralvascular disease, an atherosclerosis, Raynaud's phenomenon, anerythromelalgia and a gangrene.
 12. The method according to claim 11,wherein said peripheral vascular disease is associated with diabetes.13. The method as claimed in claim 1, wherein said patient has anormotensive blood pressure, a hypertensive blood pressure, or ahypotensive blood pressure.
 14. The method as claimed in claim 13,wherein when blood pressure is a normotensive blood pressure or ahypotensive blood pressure, said treating said patient results in astable blood pressure, or wherein when said blood pressure is ahypertensive blood pressure, said treating said patient results in adecreased blood pressure or a normotensive blood pressure. 15-30.(canceled)
 31. A topical composition for improving vascular circulationand prophylaxis or treatment of peripheral vascular disease and acondition associated with impaired blood circulation comprising: aneffective amount of a compound of formula (I):

wherein n=1 to 10; wherein R₁ is an amino acid side chain group (D or Lconfiguration), wherein R₂ is a hydrogen atom, or an amino acid (D or Lconfiguration) forming a peptide bond, or any pharmaceuticallyacceptable salts thereof; and at least one topical antimicrobial, inassociation with a pharmaceutically acceptable topical carrier.
 32. Thecomposition as claimed in claim 31, wherein said compound of formula (I)is (2-nitrooxy)-2-ethylamino-3-methylbutanoate:

or any pharmaceutically acceptable salts thereof.
 33. The composition asclaimed in claim 31, wherein said compound of formula (I) is valinebutylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.
 34. (canceled)
 35. Thecomposition as claimed in claim 31, wherein said compound of formula (I)is 2′-nitrooxyethyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.
 36. The composition asclaimed in claim 31, wherein said compound of formula (I) is4′-nitrooxybutyl 2-amino-pentanoate:

or any pharmaceutically acceptable salts thereof.
 37. (canceled)
 38. Thecomposition as claimed in claim 31, wherein R₁ is chosen from:

wherein when R₁ is

said R₁ is also linked to an NH₂ of said Formula (I) to form a prolineor hydroxyproline amino acid side chain.
 39. (canceled)
 40. Thecomposition as claimed in claim 31, wherein said topical antimicrobialis at least one of a topical antibiotic chosen from amikacin,gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin,geldanamycin, herbimycin, loracarbef, ertapenem, doripenem,imipenem/cilastatin, meropenem, cefadroxil, cefazolin, cefalotin,cefalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime,cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime,ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime,ceftobiprole, teicoplanin, vancomycin, telavancin, clindamycin,lincomycin, azithromycin, clarithromycin, dirithromycin, erythromycin,roxithromycin, troleandomycin, telithromycin, spectinomycin, aztreonam,furazolidone, nitrofurantoin, amoxicillin, ampicillin, azlocillin,carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin,methicillin, nafcillin, oxacillin, penicillin g, penicillin v,piperacillin, temocillin, ticarcillin, amoxicillin and clavulanate,ampicillin and sulbactam, piperacillin and tazobactam, ticarcillin andclavulanate, bacitracin, colistin, polymyxin b, ciprofloxacin, enoxacin,gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid,norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin,temafloxacin, mafenide, sulfonamidochrysoidine, sulfacetamide,sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole,sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim,trimethoprim-sulfamethoxazole, demeclocycline, doxycycline, minocycline,oxytetracycline, tetracycline, clofazimine, dapsone, capreomycin,cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide,rifampicin, rifabutin, rifapentine, streptomycin, arsphenamine,chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole,mupirocin, platensimycin, quinupristin/dalfopristin, rifaximin,thiamphenicol, and tinidazole, a topical antifungal chosen fromnatamycin, rimocidin, filipin, nystatin, amphotericin b, candicin,hamycin, miconazole, ketoconazole, clotrimazole, econazole, bifonazole,butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole,sulconazole, tioconazole, fluconazole, itraconazole, isavuconazole,ravuconazole, posaconazole, voriconazole, terconazole, abafungin,terbinafine, amorolfine, naftifine, butenafine, anidulafungin,caspofungin, micafungin, benzoic acid, ciclopirox, tolnaftate,undecylenic acid, 5-fluorocytosine, griseofulvin, haloprogin, and sodiumbicarbonate, and combinations thereof. 41-42. (canceled)
 43. Thecomposition as claimed in claim 31, further comprising a skinpenetration enhancer chosen from a C₈-C₂₂ fatty acid, a C₈-C₂₂ fattyalcohol, a lower alkyl ester of a C₈-C₂₂ fatty acid, a di(lower)alkylester of C₆-C₂₂ diacid, a monoglyceride of C₈-C₂₂ fatty acid,tetrahydrofurfuryl alcohol polyethylene glycol ether, polyethyleneglycol, propylene glycol, 2-(2-ethoxyethoxy)ethanol (transcutol),diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,an alkylaryl ether of polyethylene oxide, a polyethylene oxidemonomethyl ether, a polyethylene oxide dimethyl ether; dimethylsulfoxide (DMSO), glycerol, ethyl acetate, acetoacetic ester,N-alkylpyrrolidone, a terpenes, dimethyl formamide (DMF),N,N-dimethylacetamide (DMA), methyl laurate, glycerol monolaurate, afatty acid ester of a C₂ to C₄ alkanediol having a fatty acid portion ofsaid ester from about 8 to 22 carbon atoms, a fatty alcohol ether of aC₂ to C₄ alkanediols having a fatty acid portion of said ether fromabout 8 to 22 carbon atoms, triglycerides of coconut oil, isopropylpalmitate, isopropyl myristate, laurocapram, and combinations thereof.44-69. (canceled)